Neuroscience
This piece originally appeared on my Life Apps Brain & Behavior Blog on October 5, 2020.
It has been expanded on here.
This piece originally appeared on my Life Apps Brain & Behavior Blog on October 5, 2020.
It has been expanded on here.
Drug addiction is a huge problem across the world, leading to large societal costs in terms of lost productivity and healthcare expenses. In the United States (US), specifically, the National Institute on Drug Abuse (NIDA) has compiled a variety of statistics illustrating the scope of the addiction problem. Economically, the estimated annual cost of all drugs of abuse (including alcohol and tobacco) is $740 billion. Drug abuse is also a prominent problem with over 11% of those over age 12 in the US reporting using illicit drugs in the past month. Alcohol and tobacco abuse is also prevalent with nearly 6% of US adults estimated to have an alcohol use disorder (where alcohol negatively interferes with their life) and 14% of US adults report currently smoking cigarettes.
Drugs of abuse are powerfully addictive because they “hijack” biological processes put in place to ensure we continue to pursue behaviors that promote our survival. The primary biological process all drugs of abuse have in common is that their initial use results in an increase in the signaling chemical dopamine in the brain (albeit via different mechanisms based on the drug used).
Given these data, it is not surprising that in popular culture dopamine is thought of as the “reward” signal in the brain. But what exactly does that mean?
Does dopamine=reward?
What is a reward signal in the context of biology and the brain anyway?
Reward is a complex construct (for more see this excellent overview) but one reasonable definition is that reward refers to the fact that certain environmental stimuli have the ability to elicit approach responses, especially under biologically-based “need” conditions. Put another way: Stimuli that are desirable as a result of a biological need are “rewarding”.
Food is rewarding when we are hungry, water when we are thirsty.
Our brains are primed to learn about reward, specifically to learn what stimuli and actions in our environment will lead to obtaining outcomes that are necessary for survival - a process known as reinforcement learning. We learn certain behaviors are rewarding as they lead to us obtaining things we need to continue living.
Reward is a complex construct (for more see this excellent overview) but one reasonable definition is that reward refers to the fact that certain environmental stimuli have the ability to elicit approach responses, especially under biologically-based “need” conditions. Put another way: Stimuli that are desirable as a result of a biological need are “rewarding”.
Food is rewarding when we are hungry, water when we are thirsty.
Our brains are primed to learn about reward, specifically to learn what stimuli and actions in our environment will lead to obtaining outcomes that are necessary for survival - a process known as reinforcement learning. We learn certain behaviors are rewarding as they lead to us obtaining things we need to continue living.
| Reinforcement learning in its most basic form involves associating a stimulus with a response that then leads to a reward. This type of learning is done by virtually all animals. For example, a lab rat can learn that when a light comes on and it presses a particular lever in a specific environment it receives a food pellet. It learns light + press = reward via the following constituent parts: Light = stimulus Press specific lever after light = response Food pellet = reward And once this learned stimulus-response association is made, the stimulus itself can be perceived as “rewarding” in a process known as incentive salience (more on this later). |  |
Reinforcement Learning, Reward, & Addiction
Stimulus-response learning drives most of the behaviors we think of as “drug addiction” in people. When one is addicted to a drug of abuse, stimuli associated with the use of the drug (think, one’s neighborhood bar or a friend you routinely smoke with when together) can themselves drive drug use behavior. This is true even when the actual use of the drug is no longer “pleasurable” for the addicted individual. In fact, most drug addicted individuals do not find the use of their addicted drugs “pleasurable” any more.
This is because addiction is known to progress from a binge/intoxication stage of use to a withdrawal/negative affect stage and finally to a preoccupation/anticipation stage which can then reactivate drug use. Thus, drugs are initially used because they are pleasurable but over time this shifts and individuals use drugs of abuse to relieve negative withdrawal effects and not for pleasure. And, as mentioned above, drug use can be triggered by stimuli that were associated with drug use that promote preoccupation with using the drug even in individuals trying to stop or limit their use.
Stimulus-response learning drives most of the behaviors we think of as “drug addiction” in people. When one is addicted to a drug of abuse, stimuli associated with the use of the drug (think, one’s neighborhood bar or a friend you routinely smoke with when together) can themselves drive drug use behavior. This is true even when the actual use of the drug is no longer “pleasurable” for the addicted individual. In fact, most drug addicted individuals do not find the use of their addicted drugs “pleasurable” any more.
This is because addiction is known to progress from a binge/intoxication stage of use to a withdrawal/negative affect stage and finally to a preoccupation/anticipation stage which can then reactivate drug use. Thus, drugs are initially used because they are pleasurable but over time this shifts and individuals use drugs of abuse to relieve negative withdrawal effects and not for pleasure. And, as mentioned above, drug use can be triggered by stimuli that were associated with drug use that promote preoccupation with using the drug even in individuals trying to stop or limit their use.
| Why does this happen? How can a drug that starts out as pleasurable lead to negative feelings of withdrawal when not used? Well, the brain is very adaptive and quickly modifies the biological environment such that there is less disturbance in dopamine (and other chemical) signaling after drug use. So, while drugs of abuse initially result in a large release of dopamine, this effect moderates with continued use. This change in responsivity to drugs of abuse is tolerance and explains why those addicted to drugs of abuse need to take larger and larger quantities to achieve the same effect. In fact, the continued use of addictive drugs results in notable changes in the brain dopamine system (see figure at right) which promotes a strong biological dependence on them. |  Continued drug use physically changes the brain's dopamine system, which can affect drug abusers' mood & behavior. |
While these findings help us understand how the dopamine system acts in response to addictive drugs, we have yet to examine how the initial dopamine release to drugs of abuse maps onto “reward” and may promote continued early use that ultimately leads to addiction.
Does dopamine signal “reward”?
Much research has shown that dopamine does not signal “reward” (or to be more technical, pleasure) per se but rather is used in learning the various predictors of reinforcement in the environment - reinforcement learning.
This concept of dopamine signaling reinforcement learning was most famously demonstrated by the work of Wolfram Schultz, a professor at the University of Cambridge in the UK, who recorded the firing of dopamine-producing neurons (cells) in the brain of primates receiving reinforcing juice rewards.
Initially, these neurons fire to unexpected reward (juice) delivery. If a cue (tone or light) perfectly predicts the juice delivery (say 5 seconds before juice delivery), over repeated trials, Schultz found that the dopamine neurons fired in the presence of the cue (or, in psychological speech, conditioned stimulus) and not the reward. And when a reward is not followed by a stimulus previously paired with it, there is an observable dopamine “dip” locked to the time when the reward was expected to occur. See figure, below, from Schultz et al., 1997, illustrating reward prediction signaling in dopamine neurons.
Much research has shown that dopamine does not signal “reward” (or to be more technical, pleasure) per se but rather is used in learning the various predictors of reinforcement in the environment - reinforcement learning.
This concept of dopamine signaling reinforcement learning was most famously demonstrated by the work of Wolfram Schultz, a professor at the University of Cambridge in the UK, who recorded the firing of dopamine-producing neurons (cells) in the brain of primates receiving reinforcing juice rewards.
Initially, these neurons fire to unexpected reward (juice) delivery. If a cue (tone or light) perfectly predicts the juice delivery (say 5 seconds before juice delivery), over repeated trials, Schultz found that the dopamine neurons fired in the presence of the cue (or, in psychological speech, conditioned stimulus) and not the reward. And when a reward is not followed by a stimulus previously paired with it, there is an observable dopamine “dip” locked to the time when the reward was expected to occur. See figure, below, from Schultz et al., 1997, illustrating reward prediction signaling in dopamine neurons.
Reward prediction error responses at the time of reward (right) and reward-predicting visual stimuli (left in bottom two graphs). The dopamine neuron is activated by the unpredicted reward eliciting a positive reward prediction error (blue, + error, top), shows no response to the fully predicted reward eliciting no prediction error (0 error, middle), and is depressed by the omission of predicted reward eliciting a negative prediction error (- error, bottom). From Figure 2 in Schultz, 2016 and reproduced from Schultz et al., 1997. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826767/
This work can be distilled to the following conclusion:
Dopamine signals predictors of rewards and not rewards themselves.
Dopamine signals predictors of rewards and not rewards themselves.
Follow-up studies have also shown the amazing ability for dopamine-producing neurons to encode reward prediction in a scaled manner (stronger dopamine response to higher probability predictors of reward) and has resulted in perhaps the most well-accepted computational model for a biological process: the temporal difference model for reinforcement learning.
Wanting vs Liking and Dopamine’s Role in Perpetuating Addiction
This concept of dopamine as a reward predictor has been extended to a hypothesis around the role of incentive salience in dopamine release and how this process can lead to craving or wanting behaviors in those addicted to drugs of abuse.
An amazing amount of work on this topic from Kent Berridge at the University of Michigan has demonstrated dopamine release is not associated with liking in the sense of a hedonic, pleasurable response but rather dopamine motivates behavior and affects how hard animals are willing to work for rewards (“wanting”).
This concept of dopamine as a reward predictor has been extended to a hypothesis around the role of incentive salience in dopamine release and how this process can lead to craving or wanting behaviors in those addicted to drugs of abuse.
An amazing amount of work on this topic from Kent Berridge at the University of Michigan has demonstrated dopamine release is not associated with liking in the sense of a hedonic, pleasurable response but rather dopamine motivates behavior and affects how hard animals are willing to work for rewards (“wanting”).
 |  |
The processes of reinforcement learning described above naturally occur but the extra boost of dopamine release associated with taking an addictive drug further strengthens stimulus-response associations. Cues or stimuli that predict drug use can then themselves become “rewarding” and trigger wanting/craving responses in the brain as it anticipates drug use. And via other dopamine-related processes, drug use behaviors can become habitual, being guided by stimuli and the environment more than one’s active choice to use drugs.
While many may conflate liking with wanting and the role of “reward” in all of this, the implications around the role dopamine plays in these processes are critical, especially if one is working to develop treatments to combat drug addiction. Compulsive drug use despite negative consequences is what results in addictive drugs negatively interfering in someone’s life NOT the pleasure drug use provides. So, a better understanding of what processes mediate wanting and craving for drugs of abuse is essential as we seek to combat drug addiction.
 Dopamine release in three regions of the brain - the vmPFC, VS, and insula - was found to correlate with wanting more d-amphetamine. From Smith et al., 2016 https://pubmed.ncbi.nlm.nih.gov/27174408/ | My own work has sought to understand how the release of dopamine after oral d-amphetamine administration in healthy human subjects affects the brain. We found that dopamine release correlates with participants “wanting more” (NOT “liking”) d-amphetamine in three core brain regions often associated with reward and drug-related effects: ventral striatum (VS), ventromedial prefrontal cortex (vmPFC), and insula (see image at left). The VS is a core brain hub of reward valuation along with the vmPFC. Others have also found a relationship between VS dopamine release and “wanting”. The insula is a region of the brain often associated with drug craving/wanting and, in fact, damage to this part of the brain results in a loss of craving for cigarettes in smokers. Future efforts to modulate these craving-related systems and their associated dopamine signals through interventions such as transcranial magnetic stimulation may ultimately help drug-addicted individuals effectively stop their problematic drug use. |
We are just beginning to understand the neurobiological bases of drug addictive processes but continued research into them promises the development of better treatments in the future.
Concluding Thoughts
Hopefully this piece has illustrated the complex role dopamine plays in signaling reward. Research that has emerged over the last few decades using sophisticated techniques to measure brain signaling in animals and humans has implicated dopamine in reinforcement learning processes and, by extensive the incentive salience of cues associated with rewards. The role of dopamine in signaling what stimuli predict reward is hijacked and pushed into overdrive by drugs of abuse that themselves release dopamine. Thus, after repeated pairings of stimuli and drug rewards, the brain adapts to respond powerfully to drug-related stimuli and cues, prompting craving in addicted individuals.
Not everyone is as susceptible to these dopamine-mediated learning processes, though. How individual differences in biology ultimately map onto risk for drug addiction is a matter of intense interest in the field of neuroscience but is beyond the scope of this current post. For the time being, I encourage you to explore the references below for more on the complex and nuanced role dopamine plays in reward and learning processes.
Hopefully this piece has illustrated the complex role dopamine plays in signaling reward. Research that has emerged over the last few decades using sophisticated techniques to measure brain signaling in animals and humans has implicated dopamine in reinforcement learning processes and, by extensive the incentive salience of cues associated with rewards. The role of dopamine in signaling what stimuli predict reward is hijacked and pushed into overdrive by drugs of abuse that themselves release dopamine. Thus, after repeated pairings of stimuli and drug rewards, the brain adapts to respond powerfully to drug-related stimuli and cues, prompting craving in addicted individuals.
Not everyone is as susceptible to these dopamine-mediated learning processes, though. How individual differences in biology ultimately map onto risk for drug addiction is a matter of intense interest in the field of neuroscience but is beyond the scope of this current post. For the time being, I encourage you to explore the references below for more on the complex and nuanced role dopamine plays in reward and learning processes.
References:
- A Neural Substrate of Prediction and Reward
- Neurobiology of addiction: A neurocircuitry analysis
- Liking, Wanting and the Incentive-Sensitization Theory of Addiction
- Pleasure Systems in the Brain
- Learning, Reward, and Decision Making
- Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction
- Dopaminergic Mechanisms in Actions and Habits
- Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction
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